A major objective in AIDS research is to develop a vaccine to prevent HIV infection. A variety of different approaches, including envelope glycoproteins and live virus vectors, have been utilized in attempts to find models for testing anti-HIV vaccine strategies in humans. None of these approaches has given a consistent finding following virus challenge and prevention of heterologous virus infection has not been achieved. We are encouraged by the results obtained with DNA vaccines in murine models, particularly when formulated with GM-CSF and B7.2, that induce a strong cell-mediated anti-HIV immune activity. We believe that cell-mediated immunity is the most important response to block HIV replication and development of disease. Our previous studies with baboons have identified two strains of HIV-2 (UC2 and UC12) that can induce high levels of viremia and produce destructive changes in lymphoid tissue of infected animals. This primate offers an excellent model for evaluating HIV vaccines because it is susceptible to a human lentivirus, its immune system resembles that of humans, and the infected animal develops clinical signs that mirror those observed in humans. The proposed studies are directed at determining whether an HIV-2UC2 DNA vaccine will protect baboons from vaginal infection and viral pathogenesis. By using the majority of the virus genome, we expect to obtain a more effective cellular immune response than a DNA vaccine with a specific viral gene or a protein subunit vaccine. The use of cytokines and co-stimulatory molecules presented as genetic adjuvants is also included in our approach to facilitate effective cellular immunity against HIV-2 infection. Challenge will be undertaken first with the homologous virus strain used for immunization (HIV-2UC2), and if successful, with the heterologous virus strain UC-2UC12. Different routes of vaccination will also be evaluated to optimize mucosal immunity and protection. The results should provide important information about the correlates of protection against HIV infection and present approaches for developing an effective vaccine in humans.